Cardiac ubiquitin ligases: regulation and role in modulating cardiac excitation.

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Abstract A prolonged QT interval increases the likelihood for ventricular arrhythmias and sudden cardiac death. Although 16 genes have been identified in causing long QT syndrome, these mutations are rare and can therefore account for a small percentage of patients with malignant ventricular arrhythmias. Recent genome-wide association studies identified five loci associated with a prolonged QT interval. These polymorphisms may directly and cumulatively contribute to QT interval prolongation and therefore to cardiac arrhythmias. One of the aforementioned loci maps upstream of the gene coding for LITAF, which plays an important role in protein turnover. The overall goal of this study is to investigate the role of LITAF in QT interval regulation. This project will employ in vivo and in vitro experimental approaches including the use of zebrafish, cardiac specific knock out of LITAF in mice, and neonatal and adult rabbit cardiomyocytes. We hypothesize that LITAF acts as a regulator for cardiac NEDD4 ubiquitin ligases modulating cardiac excitation. Aim 1 will explore the mechanisms through which LITAF regulates L-type calcium channels and sodium channels in vivo (zebrafish and mice), whereas Aim 2 will study the mechanisms underlying the LITAF-dependent regulation of voltage-gated sodium and calcium channels in vitro, and LITAF regulation of specific NEDD4 ligases that modulate these channels.